Menopausal Hormone Therapy, Progestins & Antiprogestins

Estrogens act by binding to nuclear receptors in estrogen-responsive tissues; two estrogen receptors have been identified, in proportions that vary from tissue to tissue. Before menopause the ovarian follicle is the main source of estrogen. After menopause, most estrogen is made in peripheral tissues by converting adrenal androstenedione to estrone, and the pituitary’s LH and FSH rise; estrogen therapy brings those elevated gonadotropins back down through negative feedback.

Systemic estrogens — estradiol tablets, the Climara patch and Premarin tablets — treat moderate to severe hot flashes (vasomotor symptoms) and vulvar and vaginal atrophy due to menopause, and some also treat hypoestrogenism from hypogonadism, castration or primary ovarian failure or help prevent postmenopausal osteoporosis. The vaginal products — the Estrace cream, the Estring ring, the Vagifem insert and Premarin vaginal cream — are labeled for the vaginal symptoms of menopause (vulvar and vaginal atrophy, atrophic vaginitis). The labels set two limits: for vaginal symptoms alone, a topical vaginal product is considered first, and for osteoporosis prevention alone, non-estrogen medicines are considered first.

There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogen, and adding a progestin has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. In the presence of adequate estrogen, progesterone transforms a proliferative endometrium into a secretory one.

So a woman who still has her uterus takes estrogen with a progestin: oral micronized progesterone (Prometrium) and oral medroxyprogesterone (Provera) are both indicated to prevent endometrial hyperplasia in postmenopausal women taking conjugated estrogens. Duavee solves the same problem differently, pairing conjugated estrogens with bazedoxifene, an estrogen agonist/antagonist that acts as an antagonist in the uterus. Women taking Duavee should not take progestins, additional estrogens or additional estrogen agonist/antagonists. Progesterone and medroxyprogesterone also treat secondary amenorrhea, and the Crinone vaginal gel supplies progesterone in assisted reproductive technology.

Most of these labels carry a boxed warning drawn from the Women’s Health Initiative (WHI). Estrogen-alone therapy increased the risks of stroke and deep vein thrombosis; estrogen plus progestin therapy increased the risks of stroke, DVT, pulmonary embolism, myocardial infarction and invasive breast cancer; and in women 65 or older, both raised the risk of probable dementia. Neither should be used to prevent cardiovascular disease or dementia, and estrogens with or without progestins are prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks.

The box is product-specific. The estradiol tablet, Climara, Estrace, Vagifem, Premarin, Duavee and Provera labels carry it in their own words — Provera’s covers cardiovascular disorders, breast cancer and probable dementia with estrogen plus progestin therapy, and Duavee’s covers endometrial cancer, cardiovascular disorders and probable dementia. The current Estring and Prometrium labels state these WHI risks in their warnings without a boxed warning. Systemic exposure from the Estring ring is generally lower than from systemic estrogens, so its label says the relevance of these risks to it is not known.

Mifepristone is a progestin antagonist indicated, in a regimen with misoprostol, for the medical termination of intrauterine pregnancy through 70 days gestation. It competes with progesterone at progesterone-receptor sites, and during pregnancy it sensitizes the myometrium to the contractions prostaglandins cause; with misoprostol the regimen causes decidual necrosis, myometrial contractions and cervical softening, leading to expulsion of the pregnancy. Follow-up is needed to confirm that the termination is complete.

Its boxed warning is serious and sometimes fatal infection or bleeding, which occur very rarely after spontaneous, surgical and medical abortions. Serious infection can present atypically, without fever, and prolonged heavy bleeding may signal an incomplete abortion. Because of these risks it is available only through the Mifepristone REMS Program: prescribers are certified, patients sign a Patient Agreement Form, and it is dispensed by or under the supervision of a certified prescriber or by certified pharmacies. Mifepristone also has antiglucocorticoid activity; its use in Cushing syndrome (Korlym) belongs to the Adrenal Agents page.

Fezolinetant (Veozah) is a neurokinin 3 (NK3) receptor antagonist. It blocks neurokinin B binding on the KNDy neurons of the brain’s thermoregulatory center and is indicated for moderate to severe vasomotor symptoms due to menopause. It is not a hormone, and treatment did not show clear changes in the sex hormones measured.

Its own boxed warning is hepatotoxicity, which has occurred after marketing. Liver tests are done before starting and repeated during the first months of treatment, and the drug is stopped at once for signs of liver injury. It is contraindicated with known cirrhosis, severe renal impairment or end-stage renal disease, and with CYP1A2 inhibitors, because it is a CYP1A2 substrate.